WO1986007056A1 - Hypoglycemic thiazolidinediones - Google Patents

Hypoglycemic thiazolidinediones Download PDF

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Publication number
WO1986007056A1
WO1986007056A1 PCT/US1985/000962 US8500962W WO8607056A1 WO 1986007056 A1 WO1986007056 A1 WO 1986007056A1 US 8500962 W US8500962 W US 8500962W WO 8607056 A1 WO8607056 A1 WO 8607056A1
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WO
WIPO (PCT)
Prior art keywords
mixture
mmole
compound according
benzyl
solution
Prior art date
Application number
PCT/US1985/000962
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English (en)
French (fr)
Inventor
James F. Eggler
Gerald F. Holland
Michael Ross Johnson
Robert A. Volkmann
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to US07/010,081 priority Critical patent/US4703052A/en
Priority to HU853021A priority patent/HU210339B/hu
Priority to PCT/US1985/000962 priority patent/WO1986007056A1/en
Priority to AT86303648T priority patent/ATE50256T1/de
Priority to EP86303648A priority patent/EP0207605B1/en
Priority to DE8686303648T priority patent/DE3668892D1/de
Priority to CA000509336A priority patent/CA1279320C/en
Priority to PT82610A priority patent/PT82610B/pt
Priority to IL78831A priority patent/IL78831A/xx
Priority to GR861297A priority patent/GR861297B/el
Priority to DD86290390A priority patent/DD261154A5/de
Priority to PH33794A priority patent/PH22313A/en
Priority to IE133686A priority patent/IE58674B1/en
Priority to ES555147A priority patent/ES8707210A1/es
Priority to AU57580/86A priority patent/AU560179B2/en
Priority to KR1019860003923A priority patent/KR870000903B1/ko
Priority to ZA863762A priority patent/ZA863762B/xx
Priority to DK233586A priority patent/DK233586A/da
Priority to YU837/86A priority patent/YU44573B/xx
Priority to PL1986259633A priority patent/PL147479B1/pl
Priority to EG300/86A priority patent/EG18043A/xx
Priority to JP61117127A priority patent/JPS61271287A/ja
Priority to CN86104075A priority patent/CN1007248B/zh
Publication of WO1986007056A1 publication Critical patent/WO1986007056A1/en
Priority to FI870219A priority patent/FI89268C/fi
Priority to NO87870241A priority patent/NO166448C/no
Priority to US07/067,899 priority patent/US4738972A/en
Priority to AU75074/87A priority patent/AU583991B2/en
Priority to MYPI87001446A priority patent/MY108496A/en
Priority to PH35971A priority patent/PH25226A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • hypoglycemic agents having utility as hypoglycemic agents, methods for their use and pharmaceutical compositions containing them.
  • hypoglycemia causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death.
  • Treatment of non-insulin dependent diabetes mellitus usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin.
  • non-insulin dependent diabetes mellitus Type II diabetesl usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin.
  • hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed.
  • U.S. 4,342,771 discloses a class of oxazolidinedione hypoglycemic agents of the general formula
  • R is H or certain acyl groups and R b is certain mono- or bicyclic heterocyclic groups.
  • European Patent Application No. 117,035 discloses a group of 5-phenylthiazolidine-2,4-dione hypoglycemic agents of the formula
  • R d is H or lower alkyl and Y is an oxo or hydroxy group.
  • the present invention relates to compounds of the formula
  • R is H, CH 3 or C 2 H 5 ; when taken separately, R 1 is H, (C 5 -C 7 ) cycloalkyl, (C 6 -C 8 )methylsubstituted cycloalkyl, pyridyl, thienyl, furyl, naphthyl, p-biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, C 6 H 4 W 2 or alk-W 1 and alk is (C 1 -C 6 ) alkylene, ethylidene or isopropylidene; W 1 is H, OH, (C 1 -C 4 )alkoxy, (C 1 -C 4 ) thioalkyl, pyridyl, furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, (C 5 -C 7
  • Preferred compounds are those wherein the broken line is no bond and R is H.
  • Preferred values for R 1 , R 2 , R 3 and R 4 are R 2 , R 3 and R 4 are each H and R, is H, cyclohexyl, C 6 H 4 W 2 or alk-W 1 where alk is (C 1 -C 4 )-alkylene, ethylidene or isopropylidene;
  • W 1 is H, OH, (C 1 -C 4 ) alkoxy, cyclohexyl or C 6 H 4 W 2 and W 2 is H, F, Cl, Br, CH 3 or CH 3 O.
  • Preferred values of n are zero or 1.
  • Preferred values of X are O, S, .
  • the compounds of the invention are useful as hypoglycemic agents and are mechanistically distinct from known hypoglycemics (the sulfonylureas) currently employed in diabetic therapy.
  • Preferred invention compounds because of their excellent hypoglycemic activity in mammals are 5-[(2-benzyl-2,3-dihydrobenzofuran-5-yl)methyl]thiazolidine-2,4-dione and 5-1(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable cationic salt thereof.
  • salts as the alkali metal salts, (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), procaine, etc.
  • An especially preferred such salt is the sodium salt.
  • compositions for use in treating a hyperglycemic mammal which comprises a blood glucose lowering amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the invention further comprises a method of lowering blood glucose in a hyperglycemic mammal which comprises administering to a mammal in need of Such treatment a blood glucose lowering effective amount of a compound of formula (I).
  • the compounds of formula (I) contain asymmetric centers at the 2-position, when R 1 and R 2 are different, and at the 3-position, when R 3 and R 4 are different.
  • the compounds of formula (I) wherein the broken line is no bond have additional asymmetric centers at the R-bearing carbon atom linking the two rings, when R is methyl or ethyl; and at the 5-carbon of the thiazolidinedione group.
  • the enantiomers of a given compound one will ordinarily be favored over the others and the racemates because of its greater activity.
  • the present invention is considered to Be embracive of the racemates, diastereomeric mixtures, the pure enantiomers and diastereomers of the compounds of formula (I), the utility of which is determined by the biological evaluations described below.
  • the compounds of the invention are prepared, for example, by the method of Synthetic Scheme A, below.
  • the first step approximately equimolar amounts of the reactant (IV), wherein n, R, R 1 -R 4 and X are as defined above, and thiazolidinedione (VI) are heated in the presence of a mild base to provide the olefin of formula (III). While this step may be carried out in the presence of a reaction inert solvent, it is preferably carried out in the absence of solvent at a temperature which is sufficiently high to cause at least partial melting of the reaction mixture. A preferred such temperature is in the range of from 100 to 250° C., and especially preferred is a temperature of from 140 to 200° C.
  • suitable mild bases for the above reaction include the alkali metal and alkaline earth salts of weak acids such as the (C 1 -C 12 ) alkyl carboxylic acids and benzoic acid; alkali metal and alkaline earth carbonates and bicarbonates such as calcium carbonate, magnesium carbonate, potassium bicarbonate; and tertiary amines such as pyridine, N-methylmorpholine, N-ethylpiperidine and the like.
  • An especially preferred mild base is sodium acetate for reasons of economy and efficiency.
  • the aldehyde or ketone starting material (IV) and thiazolidinedione (VI) are combined in approximately equimolar amounts with a molar excess, preferably a 2-4 fold molar excess, of anhydrous sodium acetate and the mixture is heated at a temperature high enough to effect melting, at which temperature the reaction is substantially complete in from about 5 to 60 minutes.
  • the desired olefin of formula (III) is then isolated, for example, by mixing with water and filtration, to obtain the crude product, which is purified, if desired, e.g. by crystallization or by standard chromatographic methods.
  • the olefinic products of formula (III) are active hypoglycemic agents and also serve as intermediates for preparation of the corresponding reduced compounds of formula (II). While the reduction of the above olefins may be carried out by employing a wide variety of reducing agents which are known to reduce carbon-to-carbon double bonds, the preferred method employs hydrogen in the presence of a noble metal catalyst. Typically, the hydrogenation is carried out in the presence of a reaction inert solvent.
  • a convenient method for carrying out this transformation is to stir or shake a solution of a compound of the formula (III) under an atmosphere of hydrogen, or hydrogen mixed with an inert diluent such as nitrogen, in the presence of a noble metal hydrogenation catalyst.
  • Suitable solvents for this reaction are those which substantially dissolve the starting compound of the formula (III) but which do not themselves suffer hydrogenation or hydrogenolysis.
  • solvents examples include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate; tertiary amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; and lower alkyl carboxylic acids such as formic , acetic , propionic and isobutyric acid.
  • An especially preferred such solvent is glacial acetic acid.
  • the hydrogen gas into the reaction medium is usually accomplished by carrying out the reaction in a sealed vessel, containing the compound of formula (III), the solvent, the catalyst and the hydrogen.
  • the pressure inside the reaction vessel can vary from about 1 to about 100 kg/cm 2 .
  • the preferred pressure range, when the atmosphere inside the reaction vessel is substantially pure hydrogen, is from about 2 to about 5 kg/cm 2 .
  • the hydrogenation is generally run at a temperature of from about 0° to about 60° C, and preferably from about 25° to about 50° C. Utilizing the preferred temperature and pressure values, hydrogenation generally takes place in a few hours, e.g. from about 2 hours to about 20 hours.
  • the preferred noble metal catalysts used in this hydrogenation reaction are the type of agents known in the art for this kind of transformation, for example, nickel, palladium, platinum and rhodium.
  • a palladium catalyst is preferred because such catalysts are not readily poisoned by sulfur.
  • the catalyst is usually present in an amount from about 0.01 to about 25 weight-percent, and preferably from about 0.1 to about 10 weight-percent, based on the compound of formula (III). It is often convenient to suspend the catalyst on an inert support; a particularly convenient catalyst is palladium suspended on an inert support such as carbon.
  • the desired product of formula (II) is then isolated by standard methods, e.g. the catalyst is removed by filtration, the solvent evaporated and the product purified, if desired, by well known methods such as crystallization or by chromatography.
  • a preferred method for reduction of the compounds of formula (III) where X is S, to the corresponding compounds of formula (II), is by means of a metal-acid couple which produces hydrogen in situ.
  • a preferred such metal-acid couple for this reduction is zinc and acetic acid.
  • the pharmaceutically acceptable cationic salts of the compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base, usually one equivalent, in a co-solvent.
  • bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine.
  • the salt is isolated by concentration to dryness or by addition of a non-solvent.
  • salts can be prepared by mixing a solution of the acid with a solution of a different salt of the cation (sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired cationic salt precipitates, or can be otherwise isolated by concentration and addition of a non-solvent.
  • a solution of the acid with a solution of a different salt of the cation (sodium ethylhexanoate, magnesium oleate)
  • a solvent in which the desired cationic salt precipitates or can be otherwise isolated by concentration and addition of a non-solvent.
  • 2,4-Thiazolidinedione (VI) is commercially available.
  • the aldehydes and ketones of formula (IV) are prepared by a variety of well known methods, for example, by mild oxidation of the corresponding primary or secondary alcohol with reagents such as manganese dioxide or chromic acid under conditions known to produce aldehydes from primary alcohols and ketones from secondary alcohols; reaction of the appropriate dihydrofuran, 3,4-dihydro-2H-benzopyran, dihydrobenzothiophene or thiachroman with titanium tetrachloride in methylene chloride with 1,1-dichloromethylmethyl ether; reaction of the corresponding bromine substituted bicyclic hydrocarbon with n-butyl lithium followed by N,N-dimethylformamide at -80° to -70° C.; and other methods well known in the art.
  • Suitable eluants are common solvents such as chloroform, ethyl acetate or hexane or suitable combinations thereof which will differentiate starting materials, products, by-products, and in some cases intermediates. Applying these methods, which are well known in the art, will permit further improvement in the methodology of the specific examples detailed hereinafter, e.g. the selection of more optimal reaction times and temperatures, as well as aid in the selection of optimal processes.
  • the thiazolidine-2,4-diones of the present inven- tion are readily adapted to clinical use as antidiabetic agents.
  • the activity required for this clinical use is defined by the test for hypoglycemic effect in ob/ob mice by the following procedure:
  • Tween 80 a registered trademark of ICI America, Inc.
  • Animals were bled daily (via the ocular route) for blood metabolite levels just prior to oral administration of the test compound. The weight of each animal was recorded on days 1, 3 and 5 of the treatment.
  • the freshly collected samples (125 microliters in 330 microliter tubes) were centrifuged for two minutes at 10,000 xg at room temperature.
  • a 50 microliter sample was analyzed for glucose, for example, by the ABA 200 Bichromatic Analyzer*, using the A-gent* glucose UV reagent system # (hexokinase method) using 20, 60 and 100 mg/dl standards. Plasma glucose was then calculated by the equation,
  • the thiazolidine-2,4-diones of the present invention are clinically administered to mammals, including man, via either the oral or the parenteral route. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0.10 to about 50 mg/kg body weight of the subject per day, preferably about 0.10 to about 10 mg/kg body weight per day administered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the. most suitable dosage. This will vary according to the particular compound employed and with the subject being treated.
  • the compounds can be used in pharmaceutical preparations containing the compound, or pharmaceutically acceptable acid salt thereof, in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, conr. tain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to. form injectable solutions or suspensions.
  • injectable solutions or suspensions For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of the compounds.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in man.
  • Proton magnetic resonance spectra were measured at 60, 90, 250 or 300 MHz for solutions in deuterochloroform (CDCl 3 ) , deuterium oxide (D 2 O) , perdeutero acetone (CD 3 COCD 3 ) or perdeutero dimethyl sulfoxide (DMSO-d 6 ) and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane.
  • ppm parts per million
  • Product A is the 8-Formyl isomer of the title compound.
  • Dextrorotatory isomer Employing d-2-benzyl-6-formyl-3,4-dihydro-2H-benzopyran, [ ⁇ ] D +124.5°, provided in Example 24, as starting material, likewise affords the dextrorotatory isomer of the title compound, m.p. 257° C., M.S. 351 (M+) in 100+ percent crude yield as a yellow solid.
  • the product was found to be a mixture of sulfoxide (Rf 0.2) and the desired sulfone (Rf 0.3).
  • the sodium salt was prepared by reaction of the above product with an equimolar amount of sodium 2-ethylhexanoate in ethyl acetate, stirring the resulting mixture for one hour, evaporation of solvent in vacuo and trituration of the residue with warm hexane.
  • the sodium salt was obtained in 88% yield as a colorless solid, soluble in water and dimethylsulfoxide.
  • EXAMPLE 27 Tablets A tablet base is prepared by blending the following ingredients in the proportion by weight indicated: Sucrose, U.S.P. 80.3
  • this tablet base there is blended sufficient sodium dl-5-[2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)-methylthiazolidine-2,4-dione to form tablets containing 50 mg, 100 mg or 250 mg of active drug (weight equivalent to the free acid).
  • the portion of blend to active drug is within the limits of 1-0.167 to 1-1, e.g., in the extremes, 62.0 mg of sodium salt dihydrate and 300 mg of blend in a 50 mg tablet or 310.0 mg of sodium salt dihydrate and 250 mg of blend in a 250 mg tablet.
  • vials are filled by a freeze drying procedure. Two ml of a sterile, aqueous solution containing 286 mg/ml of sodium salt is introduced into each vial. The vials are freeze dried on trays.
  • the filtrate was diluted with an equal volume of ethyl acetate, washed with 1N sodium hydroxide, brine, dried (MgSO 4 ) and concentrated in vacuo to a yellow oil, 9.3 g, which was identified as 1-hydroxymethyl-1-(2-benzyloxyphe ⁇ yl)methylcyclohexane. This was dissolved in 150 ml dry ethanol, 600 mg 10% palladium-on-carbon catalyst was added and the mixture hydrogenated with agination at 3.5 kg/cm pressure for 18 hours. The catalyst was removed by filtration, the filtrate concentrated in vacuo to afford 5.4 g (83%) of the desired diol as a pink solid. The 1 H-NMR spectra was consistent with the structure of the title compound.
  • step (iv) By repeating the above procedures, but starting in Part (i) with 1,4-dibromobutane in pl ace of 1,3-dibromopropane afforded 7-hydroxymethyl benzo (b)-2, 3,4,5-tetrahydro-1-oxepin.
  • step (i) the tribromoether was obtained in 89% yield; in step (ii) the free acid was obtained in 72% yield, m.p. 163-165° C., purified on silica gel column, m.p. 168-169° C. The acid was not esterified, but was reduced directly by the method of Part (iii) in 94% yield to obtain the above benzoxepin as on oil.
  • Mass spectrum (m/e) 178 (M+).
  • Step (iii) This was reduced by the method of Step (iii) to provide 2- (1-methylcyclohexyl)-2,3-dihydrobenzofuran in 99% step yield, m.p. 60-63° Mass spectrum (m/e) : 216 (M+).
  • Step (ii) use of o-fluorophenylacetyl chloride in Step (ii) gave a 17% yield of 2-(2-fluorophenylmethyl)-benzofuran after purification by silica gel chromatography, viscous oil. Mass spectrum (m/e) : 226 (M+), 131.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Emergency Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
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  • Photoreceptors In Electrophotography (AREA)
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PCT/US1985/000962 1985-05-21 1985-05-21 Hypoglycemic thiazolidinediones WO1986007056A1 (en)

Priority Applications (29)

Application Number Priority Date Filing Date Title
US07/010,081 US4703052A (en) 1985-05-21 1985-05-21 Hypoglycemic thiazolidinediones
HU853021A HU210339B (en) 1985-05-21 1985-05-21 Process for preparing thiazolidinediones and their pharmaceutical compositions haring hypoglycemic effect
PCT/US1985/000962 WO1986007056A1 (en) 1985-05-21 1985-05-21 Hypoglycemic thiazolidinediones
AT86303648T ATE50256T1 (de) 1985-05-21 1986-05-14 Hypoglycemische thiazolidinedione.
EP86303648A EP0207605B1 (en) 1985-05-21 1986-05-14 Hypoglycemic thiazolidinediones
DE8686303648T DE3668892D1 (en) 1985-05-21 1986-05-14 Hypoglycemische thiazolidinedione.
CA000509336A CA1279320C (en) 1985-05-21 1986-05-16 Hypoglycemic thiazolidinediones
PT82610A PT82610B (pt) 1985-05-21 1986-05-19 Processo para a preparacao de tiazolidino-dionas hipoglicemicas
IL78831A IL78831A (en) 1985-05-21 1986-05-19 6-(thiazolidin-2,4-dion-5-ylmethyl)chromans and structurally related compounds as hypoglycemic agents
GR861297A GR861297B (en) 1985-05-21 1986-05-19 Method for the preparation of hypoglycemic thiazolidinediones
ES555147A ES8707210A1 (es) 1985-05-21 1986-05-20 Un procedimiento para la produccion de un compuesto de tiazolidindiona hipoglicemico
PH33794A PH22313A (en) 1985-05-21 1986-05-20 Hypoglycemic thiazolidinediones
IE133686A IE58674B1 (en) 1985-05-21 1986-05-20 Hypoglycemic thiazolidinediones
DD86290390A DD261154A5 (de) 1985-05-21 1986-05-20 Verfahren zur herstellung einer hypoglykaemisch wirksamen thiozolidindion-verbindung
AU57580/86A AU560179B2 (en) 1985-05-21 1986-05-20 Hypoglycemic thiazolidinedione derivatives
KR1019860003923A KR870000903B1 (ko) 1985-05-21 1986-05-20 티아졸리딘디온의 제조방법
ZA863762A ZA863762B (en) 1985-05-21 1986-05-20 Hypoglycemic thiazolidinediones
DK233586A DK233586A (da) 1985-05-21 1986-05-20 5-substituerede 1,3-thiazolidon-2,4-dion forbindelser og farmaceutiske praeparater indeholdende disse
YU837/86A YU44573B (en) 1985-05-21 1986-05-20 Process for obtaining hypoglicemic thiazolidindione
PL1986259633A PL147479B1 (en) 1985-05-21 1986-05-21 Method of obtaining novel derivatives of thiazolydinodione-2,4
EG300/86A EG18043A (en) 1985-05-21 1986-05-21 Process for preparing of thiazolidine diones
JP61117127A JPS61271287A (ja) 1985-05-21 1986-05-21 血糖降下性チアゾリジンジオン
CN86104075A CN1007248B (zh) 1985-05-21 1986-05-21 降血糖药物-噻唑烷二酮类的制备方法
FI870219A FI89268C (fi) 1985-05-21 1987-01-20 Foerfarande foer framstaellning av hypoglykemiska tiazolidindioner
NO87870241A NO166448C (no) 1985-05-21 1987-01-20 Analogifremgangsmaate for fremstilling av terapeutisk aktive tiazolidindioner.
US07/067,899 US4738972A (en) 1985-05-21 1987-06-26 Hypoglycemic thiazolidinediones
AU75074/87A AU583991B2 (en) 1985-05-21 1987-07-02 Hypoglycemic thiazolidinediones
MYPI87001446A MY108496A (en) 1985-05-21 1987-08-25 Hypoglycemic thiazolidine diones.
PH35971A PH25226A (en) 1985-05-21 1987-10-22 Hypoglycemic thiazolidinediones

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PCT/US1985/000962 WO1986007056A1 (en) 1985-05-21 1985-05-21 Hypoglycemic thiazolidinediones

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RU2186062C1 (ru) * 2001-04-09 2002-07-27 Федеральное государственное унитарное предприятие Новокузнецкий научно-исследовательский химико-фармацевтический институт Способ получения 2-бутирилбензофурана
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897393A (en) * 1987-03-18 1990-01-30 Tanabe Seiyaku Co., Ltd. Benzoxazole derivatives
US5266582A (en) * 1991-08-20 1993-11-30 Adir Et Compagnie 2,4-thiazolidinedione compounds
US5330999A (en) * 1991-08-20 1994-07-19 Adir Et Compagnie 2,4-thiazolidinedione compounds
WO2001007031A1 (en) * 1999-07-26 2001-02-01 Shionogi & Co., Ltd. Benzene derivatives and immunopotentiating compositions or drug-sensitivity restoring agents containing the same
RU2186062C1 (ru) * 2001-04-09 2002-07-27 Федеральное государственное унитарное предприятие Новокузнецкий научно-исследовательский химико-фармацевтический институт Способ получения 2-бутирилбензофурана
WO2004006916A1 (en) * 2002-07-10 2004-01-22 Applied Research Systems Ars Holding Nv Use of compounds for increasing spermatozoa motility

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ATE50256T1 (de) 1990-02-15
PH22313A (en) 1988-07-29
PH25226A (en) 1991-03-27
NO870241D0 (no) 1987-01-20
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MY108496A (en) 1996-10-31
US4703052A (en) 1987-10-27
CN1007248B (zh) 1990-03-21
JPH0586953B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1993-12-14
JPS61271287A (ja) 1986-12-01
KR860009010A (ko) 1986-12-19
GR861297B (en) 1986-09-16
FI89268B (fi) 1993-05-31
PT82610B (pt) 1988-11-30
ES8707210A1 (es) 1987-07-16
DE3668892D1 (en) 1990-03-15
FI89268C (fi) 1993-09-10
IL78831A (en) 1990-11-29
HU210339B (en) 1995-03-28
IL78831A0 (en) 1986-09-30
EP0207605B1 (en) 1990-02-07
ZA863762B (en) 1988-05-25
IE861336L (en) 1986-11-21
CA1279320C (en) 1991-01-22
AU583991B2 (en) 1989-05-11
NO870241L (no) 1987-03-20
AU560179B2 (en) 1987-04-02
PT82610A (en) 1986-06-01
FI870219L (fi) 1987-01-20
IE58674B1 (en) 1993-11-03
DK233586A (da) 1986-11-22
YU83786A (en) 1987-12-31
EP0207605A1 (en) 1987-01-07
CN86104075A (zh) 1987-03-11
AU5758086A (en) 1987-01-08
PL147479B1 (en) 1989-06-30
NO166448B (no) 1991-04-15
YU44573B (en) 1990-10-31
FI870219A0 (fi) 1987-01-20
AU7507487A (en) 1987-10-15
DK233586D0 (da) 1986-05-20
EG18043A (en) 1992-11-30
HUT45247A (en) 1988-06-28
ES555147A0 (es) 1987-07-16
DD261154A5 (de) 1988-10-19
KR870000903B1 (ko) 1987-05-04

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